https://ogma.newcastle.edu.au/vital/access/ /manager/Index ${session.getAttribute("locale")} 5 https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:13742 Wed 11 Apr 2018 16:49:24 AEST ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:29356 Tff1) gene and the tamoxifen-inducible Cre recombinase (CreERT2)–coding sequence. The resulting Tg(Tff1-CreERT2) mice were crossed with mice harboring conditional oncogenic mutations in Kras or Braf. The administration of tamoxifen to the resulting adult Tg(Tff1-CreERT2);Kras^LSL-G12D/+ and Tg(Tff1-CreERT2);Braf^LSL-V600E/+ mice resulted in gastric metaplasia, inflammation, and adenoma development, characterized by excessive STAT3 activity. To assess the contribution of STAT3 to the spontaneously developing gastric adenomas in gp130^F/F mice, which carry a knockin mutation in the Il6 signal transducer (Il6st), we generated Tg(Tff1-CreERT2);Stat3^fl/fl;gp130^F/F mice that also harbor a conditional Stat3 knockout allele and found that tamoxifen administration conferred a significant reduction in their tumor burden. Conversely, excessive Kras activity in Tg(Tff1-CreERT2);Kras^LSL-G12D/+;gp130^F/F mice promoted more extensive gastric inflammation, metaplastic transformation, and tumorigenesis than observed in Tg(Tff1-CreERT2);Kras^LSL-G12D/+ mice. Collectively, our findings demonstrate that advanced gastric tumorigenesis requires oncogenic KRAS or BRAF in concert with aberrant STAT3 activation in epithelial precursor cells of the glandular stomach, providing a new conditional model of gastric cancer in which to investigate candidate therapeutic targets and treatment strategies.]]> Wed 09 Mar 2022 16:03:09 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:23783 F/F mice. This regulation by IL-6 in gp130^F/F mice requires hyperactivation of the latent transcription factor signal transducer and activator of transcription (STAT) 3 via the IL-6 signaling receptor subunit gp130. However, the identity of LPS/TLR4-responsive inflammatory signaling pathways and gene networks, which are modulated by IL-6 (via gp130/STAT3), and the extent to which the tissue and cellular context of this regulation contributes to LPS-induced endotoxic shock in gp130^F/F mice, are unknown. We report here that in LPS-treated macrophages from gp130^F/F mice, gp130 hyperactivation upregulated the LPS-induced expression of inflammatory mediators downstream of Janus kinase (JAK)/STAT, nuclear factor κ-light-chain-enhancer of activated B cells, interferon regulatory factor and c-Jun N-terminal kinase/p38 mitogen-activated protein kinase pathways. Notably, however, LPS administration to bone marrow chimeras indicated that heightened LPS/TLR4 signaling in haemopoietic-derived gp130^F/F immune cells is dispensable for the hypersensitivity of gp130^F/F mice to LPS-induced endotoxemia. To understand the molecular consequences of gp130 hyperactivity in non-haemopoietic tissue on LPS-induced systemic inflammation, global gene expression profiling of livers from LPS-treated gp130^F/F mice was performed and identified 264 hepatic LPS-responsive genes, which are differentially regulated by hyperactive gp130 signaling. Collectively, the substantial transcriptional reprogramming of LPS-responsive genes in gp130^F/F mice emphasizes non-haemopoietic gp130 signaling as a key regulator of systemic inflammatory responses during LPS-induced endotoxemia.]]> Fri 21 Oct 2016 15:57:28 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:47318 + CD138⁺ plasma cells (PCs). Interestingly, high levels of CD138⁺ cells were also identified in the lung tissue of patients with IPF, consistent with the mouse model. Treatment of mice with bortezomib, which depletes PCs, reduced the level of Blm-induced lung fibrosis, implicating PCs as important effector cells in the development and progression of pulmonary fibrosis.]]> Fri 13 Jan 2023 11:00:15 AEDT ]]>